Diabetic Macular Edema: Changing Treatment Paradigms

J. Fernando Arevalo


Curr Opin Ophthalmol. 2014;25(6):502-507. 

In This Article

Role of Anti-vascular Endothelial Growth Factor Agents

VEGF is a key player in the pathogenesis of DME. It is elevated in both vitreous and anterior chamber, and the levels correlate with the severity of DME.[6–7] Laser photocoagulation has been the standard treatment for DME, but clinical trials have shown that targeting VEGF with ranibizumab is superior for the preservation and improvement of visual acuity.[8–9]

VEGF levels can be monitored in aqueous humor as the anterior chamber is easily accessible and vitreous and aqueous levels are highly correlated. Muether et al.[10] conducted a nonrandomized, prospective clinical study to measure VEGF levels in aqueous humor from patients with DME who were treated with ranibizumab and to determine how long VEGF was suppressed. In this clinical study, 17 eyes of 17 patients were included in the study. In total 110 aqueous humor samples were taken before an intravitreal ranibizumab injection in patients with DME. VEGF-A was measured by Luminex multiplex bead analysis (Luminex Inc., Austin, Texas, USA). This study found that VEGF was completely suppressed in all patients after ranibizumab injections for a mean of 33.7 days (SD ± 5.1, range 27–42, median 34). There was no statistically significant difference of VEGF levels at baseline and before the beginning of a new injection series (123.6 vs. 125.1 pg/ml; P = 1.0, Wilcoxon). The authors conclude that monthly ranibizumab injections lead to a complete VEGF suppression in patients with DME. The long-term stability and the range of suppression times among individuals suggest that some patients could benefit from individual injection intervals.

The 12-month, phase III, randomized, multicenter RESTORE trial (N = 345) demonstrated that ranibizumab alone or combined with laser therapy was superior to laser monotherapy in providing significant improvements in mean average change in best-corrected visual acuity (BCVA) from baseline to month 1 through month 12 (P < 0.0001).[8]

Lang et al.[11] conducted a 24-month, open-label, multicenter, phase IIIb extension study to evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in DME. The RESTORE extension study aims to provide further long-term evidence for the safety and efficacy of ranibizumab in DME. This study found that 220 patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious adverse events and adverse events were cataract (2.1%) and eye pain (14.6%), respectively. Of the patients entering the extension, four deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24, with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, central retinal thickness, and NEI VFQ-25 composite score improved from month 12 to month 24, with an average of 4.1 ranibizumab injections.

RIDE and RISE are phase III, multicenter, randomized clinical trials that enrolled a total of 759 patients with vision loss from DME, with the objective of evaluating the efficacy and safety of intravitreal ranibizumab for DME.[9]

Brown et al.[12] conducted phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. This study found that visual acuity outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained at least 15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. The incidence of serious adverse events potentially related to systemic VEGF inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. The authors concluded that the strong visual acuity gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of visual acuity improvement observed in patients originally randomized to ranibizumab.

There are fewer randomized clinical trials of bevacizumab in DME, with smaller patient numbers compared with ranibizumab. To begin to address this, the BOLT investigators have undertaken a detailed analysis of the results of their clinical trial on bevacizumab for DME (BOLT study) using the accepted outcome measures and predictive factors that have been published in the ranibizumab studies.

Sivaprasad et al.[13] conducted a randomized, prospective study to describe structural and functional changes associated with DME treated with intravitreal bevacizumab over 24 months. In this prospective, randomized trial, a post-hoc analysis of the data of 34 patients that completed 24-month follow-up in the intravitreal bevacizumab arm of a prospective, randomized controlled trial (BOLT study) was performed. This study found that the standard outcomes of mean change in BCVA and central macular thickness (CMT) in participants treated with bevacizumab were comparable to those reported in association with ranibizumab. However, exploratory analyses showed that thick maculae at baseline defined as CMT of at least 400 μm, remained significantly thicker than those less than 400 μm with intensive bevacizumab therapy, despite a comparable gain in visual acuity at both 12 and 24 months. The proportion of patients that attained a dry macula doubled in both CMT groups between the 12- and 24-month time-points.

Sivaprasad et al.[14] conducted a randomized, prospective study to explore the parameters that influence injection frequency in patients treated with intravitreal bevacizumab for DME. In this prospective, randomized trial, a post-hoc analysis of the patients randomized to the arm of a prospective, randomized controlled trial (BOLT study) was done to assess the factors that may determine the injection frequency at 12 and 24 months. This study found that eyes with better baseline visual acuity less frequently had persistent edema and had fewer recurrences in the second year. All eyes with baseline subretinal detachment showed persistent macular edema at 24 months. The authors concluded that good long-term response is predicted by resolution of macular edema by 4 months. However, approximately 20% of patients with persistent edema at 12 months achieved a dry macula, and 50% gained more than 15 letters at 24 months with sustained treatment, suggesting that edema at 4 or 12 months should not be used as a stopping criterion for treatment.

Finally, in the study period, in terms of the role of anti-VEGF in the management of DME, Nepomuceno et al.[15] conducted a randomized, prospective study to compare the visual acuity and spectral-domain optical coherence tomography (OCT) outcomes associated with intravitreal bevacizumab vs. intravitreal ranibizumab for the management of DME. This study found that 45 patients (60 eyes) completed 48 weeks of follow-up. A significant improvement in mean BCVA was observed in both groups at all study visits (P < 0.05); this improvement was significantly greater in the intravitreal ranibizumab group compared with the intravitreal bevacizumab group at weeks 8 (P = 0.032) and 32 (P = 0.042). A significant reduction in mean central subfield thickness was observed in both groups at all study visits compared with baseline (P < 0.05), with no significant difference in the magnitude of macular thickness reduction between groups. The mean number of injections was significantly higher (P = 0.005) in the intravitreal bevacizumab group (9.84) than in the intravitreal ranibizumab group (7.67). The authors concluded that intravitreal bevacizumab and intravitreal ranibizumab are associated with similar effects on central subfield thickness in patients with DME through 1 year of follow-up. Intravitreal ranibizumab is associated with greater improvement in BCVA at some study visits, and the mean number of injections is higher in the intravitreal bevacizumab group.

The studies published during this period suggest that ranibizumab is more effective than bevacizumab for the management of DME in terms of both visual acuity and anatomic outcomes. However, further studies are required to investigate the impact of intravitreal bevacizumab on retinal thickness profiles in DME.